Sulphonamides and process of making same



Patented Oct. 16, 1945 UNITED STATES PATENT OFFICE SULPHONAMIDES ANDPROCESS OF MAKING SAME No Drawing. Application July 28, 1942, Serial No.452,646. In Switzerland March 5, 1942 13 Claims.

acid radical may be converted into an amino group.

As starting products may be used, for example, 2-aminothiazoles,2-aminothiodiazoles or 2- or 4- (or -6-) aminopyrimidlnes containing twosulphonic acid radicals in which the sulphonic acid radical reactingwith the amino compound is a benzene sulphonic acid radical, whichcontains 1n the p-position an amino group or a substituent capable ofconversion into an amino group, e. g. an acylamino, -nitro or azo groupor a halogen atom, and in which the other sulphonic acid radical is theradical of a non-aromatic, i. e. an aliphatic, araliphatic, alicyclic rheterocyclic sulphonic acid. It is particularly expedient to start fromcompounds in which the nonaromatic sulphonic acid radical contains nobasic group or no substituent convertible into a basic group in theevent of the substituent capable of conversion into an amino groupcontained in the benzene sulphonic acid radical being converted into anamino group. As examples may be mentioned methyl, ethyl and benzylsulphonic acid, etc. An acylamino group may be present, however, in thebenzene sulphonic acid radical and a nitro group in the non-aromaticsulphonic acid radical. For the preparation of aminothiazoles,aminothiodiazoles and aminopyrimidines containing two sulphonic acidradicals, a non-aromatic sulphonic halide, e. g. ethyl or benzylsulphonylchloride is made to react with, for example, a 2-aminothiazole,2-aminothiodiazole or a 2-[or 4-l-aminopyrimidine, preferably in thepresence of pyridine. In this way a sulphonamidothiazole,sulphonamidothiodiazole, or sulphonamidopyrimidine is obtained, whichmay be purified by dissolving in alkali. The monosulphonamides obtainedare then treated with a p-substituted benzene sulphonyl halide, workingeither in water or in an inert organic solvent, e. g. acetone, in thepresence of alkali or, for the preparation of the pyrimidine compounds,in the presence of pyridine.

Heterccyclic amines are used for the reaction, in particularaminopyridines, aminothiazoles, aminothiodiazoles, aminopyrimidines andaminopyrazines, e. g. 2-amino-pyridine, 2-aminothiazole,2-amino-4-methylthiazole, 2-amino-4z5- dihydrothiazole,2-amino-4-oxo-5-ethyl-4 5-di- 'hydrothiazole,2-amino-5-methyl-thiodiazole, 2-

amino-5-ethylthiodiazole, 2-aminopyrimidine, 2- amino 4 methylpyrimidine, 2-amino-4z6-dimethylpyrimidine, 6-amino-24-dimethyl-pyrimidine, Z-amino-pyrazine.

The reaction should be carried out in an organic solvent, preferably inpyridine or quinoline, at a high temperature. The sulphonamides obtainedfrom the reaction are separated by the usual methods. The one can beseparated from the other, for example, after the preparation of theamino group by dissolving in acids. They may also be separated byutilizing their different solubility.

The products obtained by this process find a use as medicaments or asintermediate products in the preparation of such,

Example 1 25 parts of 2-benzylsulphonamido-thiazole,

(M. Pt. 0.), obtained by the condensation of.

45 parts of the compound so obtained are heated on a water bath for 3hours in a mixture of '10 parts pyridine and 10 parts aminothiazole. Thepyridine is distilled ofi in vacuo and the residue heated to boiling fortwo hours with dilute caustic soda. After cooling, it is filtered, ifnecessary in the presence of charcoal, and hydrochloric acid added tothe filtrate until it gives an acid reaction to Congo. The2-benzylsulphonamidothiazole of Formula III, which was used as startingproduct, separates out. It can be re-dissolved in 50% acetic acid andrecovered in the pure form (M. Pt. 175 C.) with a very good yield, whichcan then be used for a new operation. The acid mother liquors areneutralized with 'methylthiodiazole, the following compounds are 2aaeaesa sodium acetate, when 2- [p-aminobenzenesulcipitated with aceticacid. Alter treatment with phonamidol-thiazole of Formula IV is precipialittle methyl alcohol, it forms needles which tated. Onrecrystallization from dilute alcohol it melt at 177 C.

melts at 202-203" C. Example 4 The reaction in this example can bedefined as 5 It 2-amino-4-methylpyrimidine is used instead follows: 0!2-amino-4:B-dimethylpyrimidine in Example BOv-QNH-OO-CE: (I)fl-(bmylmlphonimldM-84ymgfitylamino mene'sulionyn- (II) aminothiuolo@Cflr-BOgNH-(J 3n omoomr-Q-somn-h (in (111)Z-benzylsulphonamido-thiazole2(p-aoetylaminobenzene1ulphonamido)-thlazoie (IV)2-(p-aminobenzene-sulphonamido)-thiazoie II2-benzylsu1phonamidothiodiazole or 2-ethyl- 3,2-[p-aminobenzenesulphonamido]-4-methylsulphonamidothiodiazoleisused asstarting prodpyrimidine, (M. Pt. 234 C.) is obtained in a not instead of2-benzylsu1phonamidothiazole. similar way. The latter can also beobtained by 2-lp-aminobenzenesulphonamido1-thiazo1e can heating2-[benzylsulphonimido]-3-[p-nitrobenzbe obtained in the same way.enesulphonyl]-thiazoline, melting at 172 0., ob-

Emmple 2 tained from 2-benzylsulphonamidothiazol, andp-nitrobenzenesulphonylchloride in the presence 20 parts of z-t esulphonimidol-3-[p-aceof alkali, with 2-amino-4-methyl-pyrimidine mtylaminobenzenesulphcnyl]-thiazoline, obtained pyridine and treating tproduct f the reaeas described in p e are warmed on a tion with iron andhydrochloric acid.

water bath for 4 hours with 5 parts of z-amino- What we laim i5-methylthiodiazole in 50 parts of pyri and 1. Compounds of the formula.then treated in the same way as described in 5 Example 1. Onneutralizing the mother liquors, B so which are acid to Congo, withsodium acetate, N the 2- [p-amlnobenzenesulphonamidol-5-methylthiodiazole is obtained in crystalline form. 0 1 M. Pt. 207-208C. (from dilute alcohol).

If 2-aminopyrimidine or 6-amino-2:4-di in which RSO2- represents asulphonic acid methylpyrimidine or Z-aminopyridine or 2- radical whereinthe SO2 is directly bonded aminopyrazine is used instead of 2-amino-5-to a non-aromatic carbon atom, R a member of the group consisting ofamino, acylamino,

obtained in an analogous manner: 2-[p-aminonitro, azo and halogen, and Xa member of the benzenesulphonamido]-pyrimidine (M. Pt. 255), groupconsisting of or 6 -[p aminobenzenesulphonamido] 2:4-dimethylpyrimidine(M. Pt. 237), or Z-[p-aminop 811d {1 benzenesulphonamido]-pyridine (M.Pt. 19l- 192) or 2 [p aminobenzenesulphonamidolpyrztziinci (M. Pt. 255,with decomposition) rebenzenesulphonyn thiazolmes spe vey. 3.2- ben lslhi It is also possible to start from aibenzylsulf jg g fi gf nude] 3 [pnitrobenzene acetyla'mmobenzenesulphonyl1" 4. A process for themanufacture of a suiphong iigg gg fi gg gg z'g yig gggz i' fi' amide,which comprises reacting a heteroc'yclic phonyl] th1azo1me. ammocompound with a compound of the formul Example 3 99 2.2-[benzylsulionimido] 3 [p-ao'etylamino- RSO:-N=C x 45 parts2-[benzylsulphonimido1-3-[p-acetylaminobenzenesulphonyl]-thiazoline (M.Pt. 162

C.) are heated for 1% hours to 100 C. with 11 3:2: 8; g ifi ggt' g ggggghgg gz in which R,$Oz represents a sulnhonic acid dine, the residueis treated for 2 hours on a boilradlcal wherem the so2 group is directlymg water bath with 200 parts of 10% caustic bonded toanon-aromaticallybound carbon atom. soda. parts of concentrated hydrochloric acid is f ofthe group consisting of amino' are added to the cooled solution until itgives an 70 acylammo' am and halogen and X is a acid reaction to Congo.The precipitated 2-benmember of the group consistmg ofzylsulphonamidothiazole is filtered oflf on a Buchner funnel and partsof 30% caustic soda 9 H added to the filtrate. The2-[p-aminobenzenesulphonamido]-4:6-dimethylpyrimidine is pre- 76 5. Aprocess for the manufacture of a suiphon assassa amide, which comprisesreacting a heterocyclic amino compound with a compound of the formula sx Y Hos-N G and then converting the substituent R inthe resultantproduct into an amino group.

6. A process for the manufacture of a sulphonamide, which comprisesreacting a heterocyclic amino compound in the presence of pyridine andin the heat with a compound oi the formula in which R-SOarepresents asulphonic acid radical which contains no basic group and no groupconvertible into a basic group wherein the S:- group is directly bondedto a nonaromatically bound carbon atom, R is a member of the groupconsisting of amino, acylamino'; nitro, azo and halogen, and X is amember of the group consisting of a and 1t 7. A process for themanufacture of a sulphonamide, which comprises reacting a heterocyclicamino compound in the presence of pyridine and in the heat with acompound of the formula s a-soi-n=o in which Rr-SOQ- represents asulphonic acid radical which contains no basic group and no groupconvertible into a basic group wherein the -SOagroup is directly bondedto a nonaromatically bound carbon atom, R. is a member of the groupconsisting of amino, acylamino, nitro, azo and halogen, and x is amember of the group consisting of II and l c- N and then converting thesubstituent R in the resultant product into an amino group.

8. A process for the manufacture of a sulphonamide, which comprisesreacting an aminothiazole in the presence of pyridine and in theheatwith a compound of the formula in which R-SOrrepresents a sulphonicacid radical which contains nobasic group and no group convertible intoa basic group wherein the -SO: group is directly bonded to anon-aromatically bound carbon atom, R is a member of the groupconsisting of amino, acylamiho, nitro, azo and halogen, and X is amember of the group consisting of 9. A process for the manufacture of asulphonamide, which comprises reacting an aminothiazole in the presenceoi pyridine and in the heat with a compound 0! the .i'ormula a gae. inwhich HOS- represents a sulphonic acid radical'which contains no basicgroup and no group convertible into a basic group wherein the SOagroupis directly bonded to a non-aromatically bound carbon atom, R is amember of the group consisting of amino, acylamino, nitro, azo andhalogen, and X is a member of the group consisting of and thenconverting the substituent R in the resultant product into an aminogroup.

10. A process for the manufacture of a sulphonamide, which comprisesreacting a heterocyclic amino compound in the presence of pyridine andin the heat with 2-(benzyisulphonimido) 3-(p-acylaminobenzenesulphonyl)-thiazoline, and treating the resultant product with a hydrolyzingagent.

11. A process for the manufacture, of a sulphonamide, which comprisesreacting an aminothiazole in the presence oi pyridine and in the heatwith Z-(benzylsulphonimido) -3-(p-acylaminobenzenesulphonyl)-thiazoline, and treating the resultant product with a hydrolyzingagent.

12. A process for the manufacture of a sulphonamide, which comprisesreacting a heterocyclic amino comp und in the presence of pyridine andin the heat with 2-(benzylsulphonimido) 3 (nitrobenzenesulphonyl)-thiazoline, and treating the resultant product with a hydrolyzingagent.

13. A process for the manufacture of a sulphonamide, which comprisesreacting an aminopyrimidine in the presence of pyridine and in the heatwith 2-(benzylsulphonimido) -3-(p-nitrobenzylsulphonyl)-thiazoline, andtreating tho resultant product with a hydrolyzing agent.

MAX HAR'IMANN.

FRANZ CUENI.

JEAN DRUEY.

HARAID vow MEYENBURG.

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